"It is interesting to contemplate an entangled
bank, clothed with many plants of many kinds, with birds singing on the
bushes, with various insects flitting about, and with worms crawling through
the damp earth, and to reflect that these elaborately constructed forms,
so different from each other, and dependent on each other in so complex
a manner, have all been produced by laws acting around us. These laws,
taken in the largest sense, being Growth with Reproduction; inheritance
which is almost implied by reproduction; Variability from the indirect
and direct action of the external conditions of life, and from use and
disuse; a Ratio of Increase so high as to lead to a Struggle for Life,
and as a consequence to Natural Selection, entailing Divergence of Character
and the Extinction of less-improved forms. Thus, from the war of nature,
from famine and death, the most exalted object which we are capable of
conceiving, namely, the production of the higher animals, directly follows.
There is grandeur in this view of life, with its several powers, having
been originally breathed into a few forms or into one; and that, whilst
this planet has gone cycling on according to the fixed law of gravity,
from so simple a beginning endless forms most beautiful and most wonderful
have been, and are being, evolved."

Human
behavioral genetics is controversial. Does human behavior have a genetic
component? The answer to that question is controversial in
part because ethical and legal issues make controlled studies of human
behavior difficult to devise. However, the evidence for a genetic
component in human behavior is overwhelming in spite of that limitation.

A different explanation for the controversy
is the terrible history of eugenics.
Eugenics was taken to an extreme form in Nazi Germany and forever discredited,
but it is sobering to consider consider the history of eugenics in America.
Eugenics started with Francis
Galton, a cousin of Darwin who was knighted in 1909. In the United
States it was championed by Charles B. Davenport, a Harvard-trained biologist,
Director of the Department of Experimental Evolution at Cold Spring Harbor,
and author of The Science of Human Improvement by Better
Breeding. He established the Eugenics Records Office which assembled
750,000 pedigrees and promoted the concept of eugenics with such devices
as "Fitter Families" contests at state fairs (begun in 1920). Eugenics
influenced the law in many ways, including involuntary sterilization
of mental "defectives" (30 states, beginning with Indiana in 1907), and
rules banning marriage between races (29 states, starting in 1913 and continuing
in 16 states until 1967 (!) when it was overturned by the Supreme Court
in the case of Loving v.
Virginia.)

All
behavior has heritable components. All behavior is the joint product
of heredity and environment, but differences in behavior can be apportioned
between hereditary and environment. The Canadian psychologist Donald
Hebb has likened the nature-nurture controversy to an argument about
whether the area of a rectangle depends more importantly on its width or
length. For any given rectangle the area is always a joint product
of the two dimensions. However, when comparing two rectangles having
different areas, it is meaningful to ask to what extent the different
areas can be attributed to differences in either of the dimensions.
(Note the corollary: two rectangles can have the same area but different
dimensions). Substituting, we can see that any behavior is always
the joint product of heredity and environment, but differences in
behavior can be apportioned between differences in heredity and in environment.
Having said that, it is extremely difficult to go from genes to behavior,
or more generally to bridge the chasm between genotype and phenotype. Some
single genes have major consequences for behavior. A single genes usually makes a single
protein, or sometimes only a part of a protein (for example, it takes the
products of 4 different genes to produce a single acetylcholine receptor/channel).
A typical cell expresses ~10,000 different gene products. Therefore,
if the product of a single gene differs from the prototype for that gene
because of a heritable change in the gene, we would expect the following:
Many cells will be affected--sometimes all the cells in the body (a 'housekeeping
gene').
Some cells will be affected more than others.
Consequences for the organism can range from lethality to slightly altered
performance.
Altered performance may include an improvement in performance--but that
is very rare. (Why do you
think most mutations are deleterious?)
Our knowledge of genetic effects on human is based disproportionately on
non-lethal, single gene defects that, by chance, have a distinctive consequence.Color
vision illustrates how genes give rise to mental properties. The human retina contains receptors
that transduce light into electrical signals. The signals are then
relayed via synapses to other neurons and ultimately to the brain.
Color vision is made possible by the cone receptors. You will hear
a great deal about color vision in later lectures. For a simple,
online introduction, see Breaking the Code of Color:

The importance of mutations that give
rise to color vision is that they immediately allow us to appreciate how
a change in a single gene can give rise to a fundamental change in our
mind--in the way we perceive the world. If you are male, you may
want to test your
color vision.About 7% of males have an
impairment in their ability to discriminate red-green colors. This
common, sex-linked defect is explained by the close proximity of the two
genes on the X chromosome. A much rarer condition, total colorblindness
or rod monochromacy (OMIM 216900)
must be caused by mutations in a gene common to all cones. The responsible
gene is CNGA3 (chromosome 2q11) , which encodes the alpha-subunit of the
cGMP-gated cation channel of cones (Kohl
et
al.)Huntington's
disease is a poor example to illustrate behavioral consequences of mutations. Unlike altered or
lost color vision, in which the pathway from gene to behavior is well understood,
Huntington’s
disease remains an enigma even though the gene was discovered in 1993.
Huntington's disease (or Huntington's chorea, from the dance-like movements
made by some patients) is a dominant disease: on average it affects half
of all members of a family in which one parent is affected. It is
passed on because individuals who carry the gene usually do not realize
they are affected until middle age, although onset of symptoms can vary
by more than 50 years. Both symptoms and post-mortem examination
of brains indicate that brain damage occurs most severely in the basal
ganglia, thus first affecting motor behavior but eventually affecting
cognition and death. Even though a single gene is involved, the age
of onset and time course of the disease varies greatly. About 30,000
Americans have HD. Dominant diseases usually involve
a gain of function, rather than the mere loss of a protein.
Indeed, the discovery of the gene for Huntington's disease, after a long
and much publicized search, shows that the disease results from the expansion
of a tract of repeated CAG nucleotides at the beginning of the coding region
of the gene. In normal individuals this tract is 6-39 triplets in
length, but people with Huntington’s disease have what is called a “triplet
expansion” in which the tract length increases up to 180. The
age of onset decreases as the tract length increases: so lengths of 40-55
make up the majority of adult onset cases, while expansions above 70 cause
juvenile onset. The triplet CAG codes for the
amino acid glutamine, so
the triplet expansion means that the protein will have a longer than normal
tract of glutamine at its N terminus. The protein coded by the Huntington’s
disease gene (i.e. by the gene that causes Huntington’s disease when it
is mutated) is called huntingtin.
It is a giant protein of 350 kDa, and, surprisingly, it is found in virtually
every type of cell examined. Huntingtin is an essential protein--when
it is eliminated in mice by gene targeting, the mice die as embryos.
Is function is unknown. Does Huntington’s disease provide a clue
to the function of huntingtin? Probably not, which is the reason
I indicated that Huntington’s disease is probably not a good example to
illustrate pathways from gene to mind. Although the evidence is still
incomplete, it looks as though huntingtin proteins that have extra long
glutamine terminals tend to aggregate with one another and possibly with
other proteins. This has been demonstrated in vitro by attaching
glutamine tracts of different lengths to green
fluorescent protein (GFP). In normal brains huntingtin is distributed
throughout neurons, perhaps being enriched in nerve terminals, but also
being observed in dendrites and cell bodies (and as stated before it is
in non-neural cells as well). However, in brains from people with
Huntington’s disease, and most clearly in mice expressing a transgene consisting
of exon 1 of human huntingtin with an expanded CAG repeat, the protein
(or the N-terminal fragment) is found tightly clustered within the nucleus
in close association with ubiquitin
and possibly with other proteins. At first it was thought that
these inclusions were causing cell death, but other work suggests not.
In cultured rat striatal neurons, mutant Huntingtin induced degeneration
in cultured striatal neurons but not in hippocampal neurons. Neurons
degenerated as a result of apoptosis, and cell death could be prevented
by anti-apoptotic compounds and neurotrophic factors. In these experiments,
huntingtin-induced neural degeneration was not correlated with intranuclear
inclusions (Saudou
et al, 1998). It will be fascinating to see
how this story develops, but it is highly unlikely that we will find any
special role for huntingtin in motor behavior or in cognition-- in the
sense that the color pigments play a special and essential role in color
vision.

Unforeseen
breakthroughs in molecular technology are revolutionizing the study of
genes and behavior.

In many areas of scientific advancement,
predictions of future achievements are often overstated. For example,
artificial intelligence vastly underestimated the complexity of the mental
processes it sought to simulate. However, in molecular biology, progress
has been faster than predicted. Much of the progress
has resulted from the discovery, and then rapid harnessing, of potent molecular
mechanisms. Because these tools (for example, restriction enzymes)
have evolved over billions of years, they are exceptionally well suited
for their tasks, and they can be applied with precision in the laboratory.
In addition, clever new ways of using traditional tools, and the marriage
of molecular and electronic methodologies, provide a powerful engine for
progress. Because of this, our ability to understand pathways from
gene to mind is being turned from dream to reality. Some examples
of methods are listed below.Trace
amounts of DNA can be rapidly amplified a billion fold.The process of DNA replication has
been harnessed to allow the simple amplification of huge amounts of DNA.
If a piece of single stranded DNA is placed in a mixture containing nucleotides,
DNA polymerase and appropriate ions, the strand can serve as a template
for the rapid synthesis of another strand of DNA if a short piece of complementary
DNA is also present that will anneal to the single strand and prime the
reaction.Kary
Mullis had the brilliant insight that this processes could be harnessed
by subjecting a mixture of DNA, primers and nucleotides to alternating
cycles of temperature. A high temperature (close to the boiling point
of water) causes the DNA to separate into single strands--a process called
denaturation. The temperature is then dropped to allow the primers
(short pieces of DNA, usually 20 nucleotides or so, that are complementary
to the template) to anneal to the template, and the temperature is then
raised somewhat to provide optimal conditions for incorporation of nucleotides
into the growing strand (extension). Each time this cycle is repeated,
the amount of DNA between the primers is in theory doubled. Thus,
after 30 cycles, 1 ng of DNA could produce a gram of DNA. That much
DNA is not required for most purposes, and the process is usually limited
by the amounts of ingredients added. This process, called the polymerase
chain reaction or PCR, has had a spectacular effect not only on biology,
but also on such areas as forensics (it is this method that allows the
DNA in a tiny spot of blood to be amplified and then typed, leading to
unequivocal exclusion or matching with a known sample of DNA). For
a fuller account of PCR, consult Genentech's PCR
site. The following diagram is fromGenentech's Access Excellence Site.

As an aside, Kary Mullis is not a typical Nobel Laureate.
The following is an excerpt from his autobiography in The Prix Nobel:

"My mother's parents were close to me all during my childhood,
and her father Albert stopped by to see me in a non-substantial form on
his way out of this world in 1986. I was living in California. "Pop" died
at 92 and wondering what was happening to me out in California, stopped
by Kensington for a couple days. My house afforded a view of San Francisco
and the Golden Gate Bridge. His visit was an odd experience. Not at all
frightening. I have cultivated the curious things in life and found this
one pleasant. "Pop" and I sat in the evenings in my kitchen and I told
him about the contemporary California world while we drank beer. I drank
his for him as it appeared that although he was very much there for me,
he was not there at all for the beer."

Mutations and polymorphisms in DNA can be rapidly detected.Many methods exist for detecting
mutations in DNA. The one used in our laboratory is called single
strand conformation polymorphism and heteroduplex analysis (SSCP/HD).
The name is more difficult than the method. In brief, when DNA is
denatured into single strands and is then run on a gel that allows it to
renature, each strand curls up into a distinctive conformation (or set
of conformations) that migrates at a defined rate. Surprisingly,
a change in a single nucleotide causes the conformation to differ enough
so that it can be detected as a shift in band migration. The method
is particularly good at detecting carriers of mutations, because the mutated
and normal strands migrate differently, and a portion of them anneal to
one another to form an anomalously migrating band called a hetroduplex.
Mutations probably exist in every gene within the human population. The world’s population has exceeded
6 billion people and is growing at a rate of about 2 people every second
(click here to watch).
Even given the high fidelity of DNA replication, it is expected that disabling
mutations exist in some person, somewhere, for every human autosomal gene.
For some mutations the frequency is high in certain populations: for example
about 1 in 25 Caucasians in the U. S. carry a mutation for cystic fibrosis. Recent estimates of mutation rates
suggest that they are higher than previously supposed. On average, each
person carries 4 new mutations in addition to those inherited from past
generations, and about 1.6 of these are deleterious enough to be eventually
eliminated by selection.[ref]
Virtually any known gene can be expressed in cells and its function studied. Once the sequence of a gene is known
the gene can be amplified with PCR or by growing it in bacteria.
The gene can then be linked to a promoter and placed into a circular piece
of DNA, which is then placed into cells by a variety of methods.
These cells will then express the protein from the DNA, and in that way
the function of the protein can be ascertained.
Any know gene can mutated and the consequences studied in mice. A variant of the PCR method can be
used to introduce any desired mutation into a gene, once the sequence of
the gene is known. The mutated gene can then be studied as indicated
above. A spectacular extension of this method is to mutate genes
in mouse embryonic stem cells, and then use these cells to produce
a population of mice in which some of the offspring are homozyous for the
mutated gene.Stem cells are immortal, and each
retains the ability to grow into a complete mouse when implanted into a
properly prepared donor female. Stem cells can be modified by selectively
deleting genes (gene knockouts), or adding genes (transgenics).
For gene knockouts only one copy of each paired gene is eliminated, so
the resulting cloned mice must be bred until mice are produced that are
homozygous for the deleted gene. Such mice can then be studied to determine
the consequences of this gene deletion.A catalog
of gene knockout mice lists the knockout mice using a variety of criteria.
For example, one (short) catalog lists gene knockouts that primarily affect
the nervous system. This technology is advancing rapidly, and is already
mature enough to have generated for-profit companies that will make a transgenicor
knockout mouse to your specification. One example of such a companyi s
DNX
Transgenic Sciences. Partial knockout experiments can also
produce behaviorally interesting results. For example, Beverly Koller
and her colleagues produced mice in which NMDA receptor expresssion is
partly suppressed, and report that they display a pattern of behavior that
is reminiscent of human schizophrenia. (Moln
et al., 1999).The
sequence of all human genes will soon be identified: genomics
(Please read: Genomics:
Journey to the Center of Biology) Progress in molecular biological methods
has been matched by spectacular progress in computer power, in bioinformatics,
and in machines that carry out many of the procedures. All of these
advances have made possible the industrialization of molecular-genetic
research. For example, Celera Corporation has amassed 300 high throughput
sequencing machines and is capable of decoding 140 million units of DNA
every 24 hours. This has made possible the new science of genomics,
in
which the entire genome of an organism is sequenced and all genes identified. The human genome consists of ~100,000
genes and ~3,000,000,000 paired nucleotides. Perhaps 95% of the DNA is
non-coding, leaving perhaps 150,000,000 nucleotides for the genes, or 1500
nucleotides per gene. After subtracting non-coding regions, the average
gene product would be predicted to be less than 500 amino acids in length.A
vast project to sequence the entire human genome is now underway. The origins of the
human genome project are usually traced to a 1985 meeting on human
genome sequencing held by Robert Sinsheimer at the University of California,
Santa Cruz, leading Charles DeLisi and David Smith to develop plans for
a Human Genome Initiative sponsored by the Department of Energy.
NIH funding for human genome research began in 1987. The same year, DOE
recommended a 15-year effort to map and sequence the human genome and designated
a set of specialized human genome centers. The U.S. Human Genome Project
formally began in October of 1990. In 1991 a genetic linkage map of the
entire human genome was published, based on polymerase chain reaction/Sequence-tagged
sites (PCR/STS). On 17 November 1999 the 1 billionth nucleotide
of the human genome was sequenced, and on Decmber 1, 1999 the completion
of the first chromosome (22) was announced.Spinoffs include the sequencing of
genomes of other organisms. The entire genomes of many microorganisms
have been completely sequenced and the databases can be searched via the
web. In addition the genomes of a eukaryote Saccharomyces
cerevisiae (baker's yeast)and of a multicellular organism,
the nematode Caenorhabditis
elegans have also been sequenced completely, and are available to anyone
who has access to the Internet.

The genome sequence of the fruitfly,
Drosophila
Melanogaster was recently published.
This is a landmark because the fruitfly has long served as model for genetics,
and as a bonus, "The similarities between Drosophila genes and genes
involved in human physiological processes and disease are staggering."
Jasny
& Bloom, Science. The sequence is also important because it vindicates
a very rapid sequencing strategy that should deliver a draft of the human
genome sequence later this year. Perhaps of even more importance,
the fly genome seems to use alternative splicing to a much greater extent
than either yeast or worms as a method to generate multiple proteins from
one DNA sequence, and thus produces vast complexity with fewer genes (it
has ~14,000).

You can search these databases for
any sequence of interest. The fruits of this achievement will continue
to flourish for years or decades to come. Yeast has ~6,000 genes, and C.
elegans has ~19,000 genes that probably including representatives of most
human gene families. You might think that genes in our brains would be
one set of genes not represented in these lower organisms, but in fact
a burgeoning area of research has linked a large set of genes involved
in synaptic transmission with similar genes involved in vesicular trafficking
within yeast, and insights from C. elegans should be even more useful.

From genes to mind.How can we go from genes to mind?
A common estimate is that perhaps 30% of all human genes are specific to
the nervous system. Examples of such genes are those that specify rhodopsin
and the visual pigments, genes that make ions channels needed for nerve
impulses, and genes for myriad receptors, neurotransmitters and complex
synaptic machinery. Everyone seems to be comfortable with the idea that
a single mutation can change one of the visual pigments so that color vision
is dramatically altered. Numerous other mutations are known to affect the
retina, leading to a variety of types of color blindness, night blindness,
or complete blindness. These findings are readily accepted, and can be
supported by very strong evidence.Logic suggests that other mutations
will affect central processes, with consequences for virtually any psychological
property. This proposition is not so readily accepted. Many reasons contribute
to such skepticism. Supporting evidence is nowhere near as strong as it
is for mutations that affect the retina, and the precision with which retinal
mutations can be linked to visual changes is unlikely to be matched for
most mutations that affect more central processes.But there is more to it than that,
and the residual resistance can be linked to the same kind of thinking
that finds something demeaning in the concept that we are biological machines.
We may grant machine status to the retina, but as one moves centrally,
psychological defenses become more formidable.While it is true that no link has
been established between the vast majority of genes and any psychological
property, that can be expected to change rapidly, and the rate of change
can be expected to accelerate explosively in the coming years. How
we use this new information is a central issue for modern society.Final
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